Pelvic organ prolapse represents a major health issue for women with a prevalence of 40% in postmenopausal women. Currently, the underlying pathophysiology of prolapse is not well understood and treatments are focused on end-stage disease. End-stage disease is characterized by complete protrusion of the uterus or vagina external to the body, resulting in a marked reduction in quality of life due to pelvic discomfort and bowel and bladder dysfunction. Hypotheses regarding the pathophysiology of prolapse include abnormalities in collagen and elastin, as well as alterations in smooth and skeletal muscles. Thus, genetic mutations in the extracellular matrix (ECM) and myosin pathways may result in the genesis and progression of prolapse. A study of familial prolapse identified a single nucleotide polymorphism (SNP) in the LAMC1 gene encoding laminin, an ECM component. However, this laminin mutation has not been studied in a larger, general population of women with prolapse. Given the complex nature of this disease, we hypothesize that the presence of multiple, susceptibility genes contribute to this presumed polygenic disease. Hence, we propose to study the genetic epidemiology of pelvic organ prolapse using a candidate gene association study. Our specific aims are: 1) to evaluate the association of the LAMC1 single nucleotide polymorphism (rs10911193) in a general, non-familial population of women with advanced prolapse (stage III-IV) and controls with normal support (stage 0-I), and 2) to assess the association of candidate genetic variants in functional extracellular matrix and myosin genes in women with advanced prolapse and controls. Identification of women at high risk for disease would provide a unique and exciting opportunity to initiate preventative interventions, address modifiable risk factors and individualize treatment strategies. This novel study will foster valuable collaboration between clinical scientists and geneticists and advance the implementation of translational medicine into the evolving field of urogynecology. PUBLIC HEALTH RELEVANCE: Pelvic organ prolapse, a prevalent condition in which the pelvic organs protrude external to the body, is a major health issue for women and negatively impacts quality of life. Our current understanding of the causes of prolapse is extremely limited. Identification of women at high risk through genetics research would provide a unique opportunity to implement preventative interventions and individualize treatment recommendations.